Use of peptidic conjugates for preparing compositions for alopecia preventive and curative treatment
Patent 7507719 Issued on March 24, 2009. Estimated Expiration Date: 
July 16, 2024. Estimated Expiration Date is calculated based on simple USPTO term provisions. It does not account for terminal disclaimers, term adjustments, failure to pay maintenance fees, or other factors which might affect the term of a patent.
July 16, 2024. Estimated Expiration Date is calculated based on simple USPTO term provisions. It does not account for terminal disclaimers, term adjustments, failure to pay maintenance fees, or other factors which might affect the term of a patent.Patent ReferencesCosmetic and skin treatment compositions Topical sod for treating hair loss Patent #: 5470876 InventorsAssigneeApplicationNo. 10565007 filed on 07/16/2004US Classes:514/183 or 4 peptide repeating units in known peptide chainExaminersPrimary: Tsang, CeciliaAssistant: Audet, Maury Attorney, Agent or FirmForeign Patent References
International ClassesA61K 38/00A61K 51/00 A61K 38/04 DescriptionTheinvention relates to the use of peptide conjugates containing the sequence Gly-His-Lys, for preparing dermatological or cosmetic compositions for stimulating hair growth or slowing down hair loss.Throughout the life of an individual, hair growth and hair renewal are determined by the activity of the hair follicles. They perform a regular cycle made up of three phases: anagen, catagen and telogen, which are each characterized by veryspecific molecular and cellular mechanisms: During the anagen phase which lasts approximately three years, the cells of the dermal papilla "send" signals to the stem cells present in the bulb. The competent cells that receive these signals then migrateto the hair follicle matrix; these are then referred to as matrix cells. In this region, the cells of the dermal papilla emit additional signals which allow the matrix cells to firstly proliferate and then to differentiate, which allows elongation ofthe hair shaft. During this phase, the hair follicle migrates through the dermis so as to be, in anagen VI, anchored in the hypodermis in contact with the adipose tissue. The phase that follows, called catagen, is a short phase which lastsapproximately three weeks, during which the cells of the lower part of the hair follicle enter into apoptosis, thus allowing degeneration of the hair follicle. The remaining phase, referred to as telogen, is a lag phase characterized by inactivity ofthe hair follicle for three months and loss of the hair before a further entry into the anagen phase. Since appearance is, in this day and age, an essential social factor, hair loss is a real problem which can be experienced as a social handicap by certain individuals. In man, it involves in most cases androgenic alopecia. This type of alopeciais therefore due to a deficiency in the catabolism of androgens, and more specifically of testosterone in the hair follicle by the dermal papilla cells. In fact, there is accumulation of a testosterone metabolite, DHT (a metabolite which is produced bythe action of 5α-reductase on testosterone), in the hair follicles. In a normal process, this compound is degraded and then eliminated in the urine. At the current time, 5α-reductase inhibitors are used in this type of alopecia in order toslow down hair loss. All the current knowledge concerning the biology of the hair and of the scalp, types of alopecia and conditions of the scalp, and their treatments are given in: "Pathologie du cheveu et du cuir chevelu" [Hair and scalp pathology] P. Bouhanna andP. Reygagne--publishers Masson. For many years, in the cosmetics or pharmaceutical industry, there has been a continuing search for substances that make it possible to eliminate or reduce the effect of alopecia, and in particular to induce or stimulate hair growth or todecrease hair loss. A certain number of compounds are already used, such as minoxidil or finasteride. Some peptides are known for their stimulatory action on hair growth; however, no document discloses the fact that the peptide conjugates described hereinafter are useful in the preventive and curative treatment of alopecia. A subject of the present invention is therefore the use of a peptide corresponding to general formula (I) TABLE-US-00001 X-Gly-His-Lys-Y (I) (SEQ ID Nos. 1-2) or of the conjugate thereof corresponding to general formula (II) TABLE-US-00002 A-X-Gly-His-Lys-Y (II) (SEQ ID Nos. 3-4) in which A represents the radical corresponding to a monocarboxylic acid of general formula (III) HOOC--R (III) in which R represents a linear or branched C1-C.sub.24 aliphatic radical optionally substituted with a hydroxyl group, possibly containingone or more unsaturations, advantageously from 1 to 6, lipoic acid or its reduced form, dihydrolipoic acid, N-lipoyl-lysine or else retinoic acid, X represents a chain of 1 to 3 Lys residues, that are optionally methylated, or, when the formula isformula (II), a bond, Y represents an --OH or --NH2 group, the amino acids being in D, L or DL form, or else A-X represents a hydrogen atom, for preparing a cosmetic or dermatological composition for use in the preventive and curative treatment ofalopecia. Advantageously, the peptide sequence is chemically or physically conjugated with the acids A. The conjugated peptides according to the invention are bonded in the form of salts, of esters, or of amides to these acids A, the carboxylic acidfraction of the acid providing the bond. The amino acids in the peptide of formula (I) or the peptide conjugate of formula (II) may have a D, L or DL configuration. In other words, the peptides of formula (I) and the peptide conjugates of formula (II) can contain one or more asymmetrical carbon atoms. They can therefore exist in the form of enantiomers or of diastereoisomers. These enantiomers anddiastereoisomers, and also the mixtures thereof, including racemic mixtures, are part of the invention. The peptide conjugates of formula (II) are low-molecular-weight derivatives which are obtained in the form of amides of the compound of formula (III). In addition, the peptides of formula (I) and the peptide conjugates of formula (II) can be coupled with zinc, in the form of salts, so as to form complexes. The peptides and the peptide conjugates thereof, and also the synthesis thereof, are described in European Patent EP 869 969. They are described therein as being useful in the treatment, by topical application, of chronic wound healing, esthetichealing of surgical wounds, and the preventive and curative treatment of stretch marks and of complications thereof. Their use in the cosmetology field, in particular in the preventive and curative treatment of wrinkles on the face, the neck and thehands, is also disclosed therein. In the context of the present invention: the term "Lys" is intended to mean lysine or a halogenated derivative of lysine, such as dihydrobromomethyllysine, the term "MeLys" is intended to mean methyllysine (methylation in the 6-position), theterm "His" is intended to mean histidine, the term "Gly" is intended to mean glycine or an alkylated derivative thereof, such as methylglycine. It is also specified that the peptides of formula (I) or the peptide conjugates of formula (II) mentioned above, and the use of which is the subject of the present invention, can be obtained in the NH2-terminal form (in other words,exhibiting an amide function) and in the OH-terminal form (in other words, exhibiting a carboxylic acid function). Preferably, the acid of formula (III) is a polyunsaturated fatty acid, i.e. containing from 1 to 6 unsaturations. Even more preferably, it is an omega-3 acid. Among these omega-3 acids, mention may in particular be made of α-linolenic acid, cervonic acid, timnodonic acid and pinolenic acid. Cervonic acid, timnodonic acid and pinolenic acid are also known under the respective names:4,7,10,13,16,19-docosahexaenoic acid (DHA), 5,8,11,14,17-eicosapentaenoic acid (EPA) and 5,9,12-octodecatrienoic acid. When A represents a monocarboxylic acid of general formula (III), it may be advantageously chosen from acetic acid, myristic acid, palmitic acid, and hydroxy-decenoic and decenoic acids, and in particular trans-10-hydroxy-Δ2-decenoic acidand trans-oxo-9-decen-2-oic acid. Among the peptide conjugates of the invention, mention may be made of the following peptide conjugates: TABLE-US-00003 1- A-MeLys-Lys-Lys-Gly-His-Lys-NH2, (SEQ ID No. 5) 2- A-MeLys-Lys-Gly-His-Lys-NH2, (SEQ ID No. 6) 3- A-MeLys-Gly-His-Lys-NH2, (SEQ ID No. 7) 4- A-MeLys-Lys-Lys-Gly-His-Lys-OH, (SEQ ID No. 8) 5-A-MeLys-Lys-Gly-His-Lys-OH, (SEQ ID No. 9) 6- A-MeLys-Gly-His-Lys-OH, (SEQ ID No. 10) 7- A-Lys-Lys-Gly-His-Lys-NH2, (SEQ ID No. 11) 8- A-Lys-Gly-His-Lys-NH2, (SEQ ID No. 12) 9- A-Lys-Lys-Gly-His-Lys-OH, (SEQ ID No. 13) 10- A-Lys-Gly-His-Lys-OH. (SEQ ID No. 14) The peptide conjugates for which A is chosen from lipoic acid and acetic acid are most particularly suitable in the context of the present invention. Mention may also be made of the following peptide conjugates: TABLE-US-00004 Peptide R H-Gly-His-Lys-OH, Peptide S Lipoyl-Lys-Gly-His-Lys-NH2, (SEQ ID NO: 12) Peptide V Ac-Lys-Gly-His-Lys-NH2. (SEQ ID NO: 12) The peptides or the peptide conjugates thereof can be administered topically for their cosmetic use. They can also be used orally in food supplements, in other words in the nutraceutic field. They are preferably administered topically. The peptide conjugate may be present, in a topical cosmetic composition, at a concentration of between 10-8 and 10-3 M, preferably of between 10-7 and 10-5 M. The cosmetic or dermatological composition may, for example, be in the form of a lotion, of a treating shampoo, of a spray, of a gel or of a treating cream. Another subject of the present invention concerns the method of cosmetic treatment for combating hair loss, comprising the application to the scalp of a composition comprising a peptide conjugate as described above, optionally in combination asdescribed hereinafter. They can be administered alone or in combination with compounds that further enhance the activity on regrowth and that have already been described for this activity. Among these compounds, mention may be made of: minoxidil, nicotinic acid esters, anti-inflammatory agents, more particularly peptides with anti-inflammatory activity, retinoic acid, derivatives thereof and retinol, 5α-reductase inhibitors. Other peptides or peptide conjugates can also be combined with the peptides or peptide conjugates whose use is the subject of the present invention. They correspond to the formulae TABLE-US-00005 W-Lys-Asp-Val-Z (I) (SEQ ID Nos. 15-16) or the peptide conjugate thereof corresponding to formula (II) TABLE-US-00006 A-W-Lys-Asp-Val-Z (II) (SEQ ID Nos. 17-18) in which A has the same definition as that given above, and W represents Glu-Gln-Arg, Arg-Lys, Arg-Lys-Asp, Arg or a bond, when Z represents Tyr-Val-Gln-Leu-Tyr-NH2(SEO ID NO: 19), Leu-DOPA, DOPA-NH2 or HomoPhe-NH2, or else Wrepresents Gly-Gln-Gln or Glu-Gln, when Z represents Tyr-Val-Gln-Leu-Tyr-NH2(SEO ID NO: 19), Leu-DOPA, Val-Tyr-OH, Val-Tyr-NH2, Tyr-NH2, Tyr-OH, DOPA-NH2 or HomoPhe-NH2, in the form of enantiomers or of diastereoisomers, and alsothe mixtures thereof, including racemic mixtures, and the complexes with zinc which can be formed with these peptides or peptide conjugates. The term "DOPA" is intended to mean dihydroxyphenyl-alanine and the term "HomoPhe" is intended to mean homophenylalanine. Finally, one or more UVB-screening agents can also be combined with the peptides or with the peptide conjugates whose use is the subject of the present invention, when a topical administration is involved. They allow photoprotection of thescalp. Thus, among suitable UVB-screening agents, mention may be made, given as their INCI name, of: p-aminobenzoic acid or PABA and its esters: Ethylhexyl dimethylPABA PEG-25 PABA cinnamates: Ethylhexyl methoxycinnamate Isoamyl p-methoxycinnamateOctoacrylene salicylates: Homosalate Ethylhexyl salicylate benzimidazoles: Phenylbenzimidazolesulfonic acid benzylidenecamphor derivatives 4-Methylbenzylidenecamphor Benzylidenecamphor Camphor benzalkonium methosulfatePolyacrylamidomethylbenzylidenecamphor triazines: Ethylhexyl triazone Diethylhexyl butamido triazone. The peptides and peptide conjugates whose use is the subject of the invention were the subject of pharmacological trials making it possible to show their anti-hair loss activity. Effects of the Various Peptides on the Growth of Mouse Vibrissae In Vitro In order to show the stimulatory effect of the peptides on hair growth, anagen-phase hair follicles of mouse vibrissae are cultured according to the technique described by Philpott (Philpott et al. 1994, Human Hair growth in vitro: a model forthe study of hair biology. Journal of dermatological science 7; S55-S72). The growth of the hair follicle shaft was followed for several days (D0 to D4). The results are reported in the table below for the peptides R, S and V described above. Theseresults show that these peptides stimulate hair growth when the hair follicles are kept alive in vitro. TABLE-US-00007 Peptide R Peptide S Peptide V Control 10-7 M 10-7 M 10-7 M D0 0.00 0.00 0.00 0.00 D1 0.3 0.8 0.77 0.86 D2 0.4 1.27 1.47 1.34 D3 0.5 1.38 1.72 1.65 D4 0.5 1.38 1.86 1.65 The following formulation examples illustrate the present invention. EXAMPLE 1 Lotion Comprising the Peptide Conjugate Ac-Lys-Gly-His-Lys-NH2 (SEQ ID NO: 12) TABLE-US-00008 (in g) Peptide Ac-Lys-Gly-His-Lys-NH2 5 × 10-6 95° ethanol 60 Propylene glycol 10 Water - preserving agents - fragrance qs 100 EXAMPLE 2 Lotion Comprising the Peptide Conjugate Lipoyl-Lys-Gly-His-Lys-NH2 (SEQ ID NO:12) TABLE-US-00009 (in g) Peptide Lipoyl-Lys-Gly-His-Lys-NH2 10-5 Water 81 Keltrol T 0.5 Techpolymer MB-4C 1 Sepigel 305 0.5 Silicone oil 0.2 1401 2 Butylene glycol 5 > PRT Artificial sequenceDescription of Artificial Sequence Synthetic peptide aa Xaa Gly His Lys PRT Artificial sequence Description of Artificial Sequence Synthetic peptide 2 Xaa Xaa Xaa Gly His Lys PRT Artificial sequence Description of ArtificialSequence Synthetic peptide 3 Xaa Xaa Xaa Gly His Lys PRT Artificial sequence Description of Artificial Sequence Synthetic peptide 4 Xaa Xaa Xaa Gly His Lys PRT Artificial sequence Description of Artificial Sequence Synthetic peptide 5 XaaLys Lys Gly His Lys PRT Artificial sequence Description of Artificial Sequence Synthetic peptide 6 Xaa Lys Gly His Lys PRT Artificial sequence Description of Artificial Sequence Synthetic peptide 7 Xaa Gly His Lys RT Artificialsequence Description of Artificial Sequence Synthetic peptide 8 Xaa Lys Lys Gly His Lys PRT Artificial sequence Description of Artificial Sequence Synthetic peptide 9 Xaa Lys Gly His Lys 4 PRT Artificial sequence Description of ArtificialSequence Synthetic peptide Gly His Lys PRT Artificial sequence Description of Artificial Sequence Synthetic peptide Lys Gly His Lys 4 PRT Artificial sequence Description of Artificial Sequence Synthetic peptide Gly HisLys PRT Artificial sequence Description of Artificial Sequence Synthetic peptide Lys Gly His Lys 4 PRT Artificial sequence Description of Artificial Sequence Synthetic peptide Gly His Lys PRT Artificial sequenceDescription of Artificial Sequence Synthetic peptide Xaa Xaa Lys Asp Val Xaa Xaa Xaa Xaa Xaa RT Artificial sequence Description of Artificial Sequence Synthetic peptide Xaa Xaa Lys Asp Val Xaa Xaa Xaa Xaa Xaa RTArtificial sequence Description of Artificial Sequence Synthetic peptide Xaa Xaa Lys Asp Val Xaa Xaa Xaa Xaa Xaa RT Artificial sequence Description of Artificial Sequence Synthetic peptide Xaa Xaa Lys Asp Val Xaa Xaa Xaa XaaXaa T Artificial Sequence Description of Artificial Sequence Synthetic peptide Val Gln Leu Tyr > Other References
Field of Search3 or 4 peptide repeating units in known peptide chain |
